Despite concerted efforts to improve therapy, five year survival rates for patients with advanced stage oral squamous cell carcinoma (oral SCC) remain discouragingly low. Early detection combined with strategies for local intervention, such as chemoprevention prior to oral SCC development, could dramatically improve clinical outcomes. Results of previously conducted oral cavity chemoprevention trials, however, have not been highly promising. Notably, the majority of previous oral chemoprevention trials administered agents systemically. For targeted disease management, local delivery methods have several advantages relative to systemic administration that include delivery of therapeutically relevant concentrations directly to the lesional site. Recent studies from our laboratories have shown that black raspberries possess cancer preventing properties at both the in vitro and in vivo levels. Dietary administration of freeze-dried black raspberries (FBR) successfully inhibited both esophageal and cheek pouch carcinoma in animal models. Likewise, in vitro studies have shown both FBR and black raspberry extracts regulate cell growth by a variety of mechanisms that include scavenging of reactive species, initiation of apoptosis and induction of differentiation. For persons with the premalignant condition, oral epithelial dysplasia, chemoprevention will likely be necessary for the remainder of their lives. Therefore, identification of nontoxic, effective agents delivered in formulations that provide maximal concentrations at the lesional site, is necessary to improve patient prognosis. Based on our results we hypothesize that berry gels elicit their chemopreventive effects by attenuation of proinflammatory and proproliferative pathways while concurrently stimulating growth regulatory mechanisms such as differentiation and apoptosis. We also speculate that oral mucosal phytochemical metabolism modulates chemopreventive effects of the topically applied parent compounds. Specific Aim 1 studies will evaluate the ability of optimized berry gel formulations to affect: 1) tissue generation of reactive species, 2) production of proangiogenic molecules, and 3) proliferation, differentiation and apoptotic indices of surface oral epithelium. Studies proposed for Specific Aim 2 will evaluate the capacity for human oral mucosa to: 1) metabolize selected FBR phenolic compounds, 2) modulate chemopreventive properties of FBR parent compounds. Public health relevance: These studies will test bioadhesive gels, which contain naturally occurring cancer fighting compounds to determine the gels'chemopreventive (cancer preventing) abilities on oral tissues. Oral cancer remains a significant health problem in the U.S. Even for those persons who can be cured, the necessary surgery is debilitating and often disfiguring. These studies will test the effects of bioadhesive gels, which contain naturally occurring cancer fighting compounds, to determine the gels'chemopreventive (cancer fighting) abilities on explants of human oral mouth tissues.